BACKGROUND:Monoclonal antibodies (mAbs) and their derivatives represent a central pillar of contemporary oncology, with expanding complexity in molecular design and clinical application. Beyond unconjugated mAbs, bispecific antibodies (bsAbs), trispecific antibodies (tsAbs), and antibody-drug conjugates (ADCs) introduce additional pharmacological dimensions that directly impact efficacy, toxicity, and resistance. BsAbs were developed as pharmacological matchmakers to simultaneously engage tumor antigens and immune receptors, physically bridging effectors and malignant cells to promote immunological synapse formation. TsAbs extend this concept by enabling coordinated engagement of three targets. ADCs exploit mAb specificity to deliver highly potent, otherwise intolerable cytotoxic payloads directly into tumor cells, expanding the therapeutic window in hematologic and solid tumors. SUMMARY:Clinical performance is tightly linked to molecular architecture: bsAb/tsAb activity depends on valency, target geometry, and Fc configuration, whereas ADC efficacy reflects a tripartite pharmacology integrating target engagement, intracellular payload release, and bystander cytotoxicity. Despite their remarkable potency, antibody-based platforms remain vulnerable to resistance, which may arise through target-dependent mechanisms, including antigen downregulation and epitope masking, or target-independent processes, such as altered intracellular trafficking, lysosomal dysfunction, payload efflux, and adaptive survival signaling. KEY MESSAGE:A comprehensive understanding of antibody architecture, target biology, pharmacokinetic/pharmacodynamic behavior, toxicity profiles, and resistance mechanisms is essential to optimize treatment selection and sequencing. Collectively, mAbs, bsAbs/tsAbs, and ADCs provide the mechanistic and technological basis for next-generation platforms, including peptide-drug conjugates and antibody-radionuclide conjugates.
INTRODUCTION:Pseudoprogression during immunotherapy (IO) - defined as clinical documentation of tumor growth or new lesions during treatment with immune checkpoint inhibitors, followed by disease regression - has been reported in ≤10% of cases. Its incidence appears to be lower in cutaneous squamous cell carcinoma (cSCC) patients (1.5-4%). CASE PRESENTATION:We report a rare case of pseudoprogression of an advanced cSCC during IO (cemiplimab). Following initial surgery for a cSCC of the left auricular area, the tumor recurred and infiltrated the ear cartilage and external auditory meatus. At the time of administration of the second IO, the tumor had rapidly grown with a fulminant pattern and doubled in size. Treatment with IO continued, as per protocol, and by the third infusion appointment, the tumor had disappeared, and complete re-epithelialization of the auricular area was observed, confirming pseudoprogression. So far, the patient has received ten cycles of IO without experiencing toxicity, and there has been no sign of disease recurrence. CONCLUSION:Awareness of potential pseudoprogression is crucial for clinicians managing advanced cSCC with cemiplimab.
INTRODUCTION:The introduction of enfortumab vedotin plus pembrolizumab (EVP) has caused a paradigm shift in the first-line treatment strategies for metastatic urothelial carcinoma (mUC). However, no standard subsequent therapy has been established after EVP therapy, and the role of platinum-based chemotherapy (PBC) followed by avelumab maintenance therapy remains unclear. CASE PRESENTATION:We report three cases of mUC treated with EVP followed by PBC and subsequent avelumab maintenance therapy. As the first-line treatment, EVP achieved disease control in all cases; however, disease progression or treatment discontinuation occurred. Subsequent PBC resulted in stable disease or partial response. Afterward, patients were transitioned to avelumab maintenance therapy, which resulted in further tumor regression or sustained disease control, even in patients with prior pembrolizumab exposure and those who discontinued EVP therapy due to adverse events. CONCLUSION:PBC is often considered as a subsequent treatment after EVP therapy, except in patients with FGFR gene alterations. PBC followed by avelumab maintenance therapy may represent a feasible subsequent treatment option for selected patients with mUC who achieve disease control after EVP therapy.
INTRODUCTION:Drug-resistant tuberculosis presents a major global health challenge due to limited therapeutic options and significant toxicity of traditional regimens. Linezolid, a core Group A drug per WHO guidelines, demonstrates high efficacy but its optimal dosing is debated due to dose-dependent adverse effects. This study aimed to evaluate the efficacy and safety of different initial doses of linezolid combined with bedaquiline for treating drug-resistant pulmonary tuberculosis. METHODS:This retrospective study analyzed patients with drug-resistant tuberculosis treated with bedaquiline and linezolid in China from June 2019-June 2022. The data originated from medical records. Adverse drug reactions were categorized using the Common Terminology Criteria for Adverse Events (v5.0). Three groups were formed based on the initial linezolid dose: 1,200 mg/day (high-dose, n = 99), 600 mg/day (low-dose, n = 121), and 0 mg/day (control, n = 50). Clinical data, epidemiological characteristics, treatment outcomes, adverse events, and prognoses of these groups were compared and analyzed statistically. RESULTS:Our research scrutinized the effects of different initial doses of linezolid and bedaquiline on drug-resistant tuberculosis. No significant differences were noted between high-dose and low-dose groups in 6 months for sputum smear negativity, cavitary closure time, or time for lesion resorption and reduction. However, a higher incidence of adverse events was observed in the high-dose group (47.47%) compared to the low-dose group (29.75%), with myelosuppression, peripheral neuritis, and optic neuritis being predominant. Notably, the proportion of patients requiring dose adjustment due to adverse events was significantly higher in the high-dose group (74.47%) than in the low-dose group (50%, p = 0.021). CONCLUSIONS:Initial daily linezolid dose of 600 mg and 1,200 mg in combination with bedaquiline yields equivalent efficacy for drug-resistant pulmonary tuberculosis. The lower dose demonstrates improved tolerability. For the said therapy, we advocate a primary recommendation of a daily linezolid dose of 600 mg.
BACKGROUND:Critically ill patients exhibit acute physiological changes leading to marked antibiotic exposure variability and an increased probability of either subtherapeutic or potentially toxic exposures. Beta-lactam antibiotics are often affected by these physiological changes, leading to variable and often subtherapeutic exposures. Therefore, methods to increase the probability of a therapeutic exposure may be beneficial for critically ill patients. Model Informed Precision Dosing (MIPD) is an emerging strategy using advanced computer models to individualise dosing in this vulnerable population with or without therapeutic drug monitoring (TDM). By tailoring therapy to the individual patient scenario, MIPD aims to improve clinical outcomes by enhancing the likelihood of effective and safe therapy. SUMMARY:MIPD-guided beta-lactam antibiotic dosing may improve the probability of attaining target therapeutic exposures and clinical cure rates compared to standard fixed dosing in critically ill patients. Moreover, MIPD allows clinicians to target higher beta-lactam antibiotic exposures while minimising the risk of toxicity, when the goal of treatment is both improving clinical cure rates and suppressing the probability of antibiotic resistance emergence. No differences in mortality and adverse event reduction compared to standard dosing have been currently identified in the literature. However, the exact potential of MIPD has yet to be determined given the significant limitations in the current evidence base, including heterogeneous study designs, small sample sizes, inconsistent implementation strategies, and variable outcome definitions. Clinical practice and future research should optimise MIPD performance by selecting appropriate and innovative beta-lactam antibiotic exposure models, as well as identify methods to instigate early MIPD dosing and timely TDM dose adjustments. This may further improve clinical and economic outcomes for critically ill patients. KEY MESSAGES:MIPD is a clinical decision making tool that uses pharmacokinetic modelling to guide beta-lactam dosing, with or without TDM input. A small number of observational and randomised beta-lactam MIPD intervention studies suggest that clinical outcomes for critically ill patients are improved. Technical, casemix, implementation, and study design limitations likely contribute to inconsistent findings in studies comparing MIPD to standard care. Stronger signals in improved outcomes are correlated with appropriate pharmacokinetic model and pharmacokinetic/pharmacodynamic (PK/PD) target selection, accompanied with timely dose adjustments in critically ill patients with significant pharmacokinetic variability and/or complex pharmacodynamic profiles. Future studies should more robustly define key features that will optimise patient outcomes including: optimal target exposure, characteristics of patients most likely to benefit, preferred minimum inhibitory concentration (MIC) parameter, favoured beta-lactam infusion duration, MIPD technical and implementation factors, and study design elements.
INTRODUCTION:Toosendanin has shown anticancer activity in various malignancies, including gynecological cancers. As tamoxifen is a cornerstone therapy for breast and ovarian cancers, this study investigated how toosendanin alters its pharmacokinetics, with the goal of assessing interaction risks and supporting drug development. METHODS:A pharmacokinetic study was performed in female Sprague-Dawley rats. The rats received an oral dose of tamoxifen (10 mg/kg), with or without pretreatment with toosendanin (30 or 60 mg/kg). Plasma concentrations of tamoxifen were determined by LC-MS/MS. The effects of toosendanin on the metabolic stability of tamoxifen and cytochrome P450 enzyme (CYP450) activity were investigated using liver microsomes. RESULTS:Toosendanin significantly altered the pharmacokinetic profile of tamoxifen. Concomitant administration of toosendanin (30 and 60 mg/kg) resulted in a dose-dependent increase in the maximum plasma concentration of tamoxifen from 120.67 ± 7.50 to 186.67 ± 6.44 and 235.00 ± 15.96 µg/L, respectively. The half-life was prolonged from 12.55 ± 0.57 to 14.46 ± 0.96 and 16.55 ± 1.02 h, while the clearance rate decreased from 4.92 ± 0.24 to 3.04 ± 0.14 and 2.10 ± 0.07 L/h/kg, respectively. In vitro studies further revealed that toosendanin inhibited the metabolic stability of tamoxifen, as evidenced by a reduction in its intrinsic clearance from 45.36 ± 1.92 to 34.48 ± 1.92 and 28.44 ± 1.21 µL/min/mg protein. Furthermore, toosendanin exhibited a half-maximal inhibitory concentration of 11.50 µm for CYP2D6 activity. CONCLUSION:This study demonstrates that toosendanin alters the pharmacokinetics of tamoxifen, likely by inhibiting its metabolic stability and CYP2D6 activity. This interaction leads to a potentially significant pharmacokinetic risk when toosendanin is co-administered with tamoxifen, potentially potentiating its exposure.
INTRODUCTION:Epiploic appendagitis is an uncommon cause of acute abdominal pain, often mimicking surgical emergencies. This case highlights the diagnostic process for epiploic appendagitis in a breast cancer patient receiving abemaciclib, a CDK4/6 (cyclin-dependent kinase) inhibitor, and discusses potential associations with targeted therapies. CASE PRESENTATION:We present a case of a 48-year-old female on adjuvant abemaciclib for stage IIIA breast cancer who developed acute left iliac fossa pain. Clinical assessment, laboratory investigations, transvaginal ultrasound, and subsequent computed tomography (CT) imaging of the abdomen and pelvis were performed to establish the diagnosis. CT imaging revealed a characteristic ovoid fat-density lesion with surrounding inflammation adjacent to the sigmoid colon, consistent with epiploic appendagitis. Other differential diagnoses, including ovarian pathology and diverticulitis, were excluded. The patient was managed conservatively with analgesia, and the abemaciclib was temporarily discontinued and restarted at a lower dose, leading to symptom resolution. This case underscores the importance of considering epiploic appendagitis in the differential diagnosis of acute abdominal pain, particularly in patients on targeted therapies like abemaciclib, which are known to have gastrointestinal side effects. Timely and accurate diagnosis via imaging avoided unnecessary surgical intervention. CONCLUSION:This case is the first of its kind to propose a novel association between the use of targeted therapies such as abemaciclib and the development of inflammatory conditions such as epiploic appendagitis. It emphasises the crucial role of clinical suspicion and appropriate imaging in establishing this rare diagnosis. Further research is warranted to explore potential links between CDK4/6 inhibitors and the development of epiploic appendagitis.
BACKGROUND:Targeted therapies have revolutionized the treatment of hematological malignancies, offering improved efficacy with fewer off-target effects compared to traditional chemotherapy. However, significant pharmacokinetic (PK) and pharmacodynamic (PD) variability exists among patients receiving these therapies. SUMMARY:Therapeutic drug monitoring (TDM) measures drug exposure and thereby helps to adjust the dose of a drug to maintain its concentration within a target range. It is frequently applied for drugs with characteristics like PK variability or narrow therapeutic window, among others, to ensure optimal therapeutic outcome while minimizing adverse effects. Many molecular targeted agents (MTAs) for malignancies, especially tyrosine kinase inhibitors, exhibit significant variability in exposure, and yet are still dosed with a "one-size-fits-all" approach. While this is partially culprit to regulatory approval requirements of MTA, it contradicts principles of targeted therapy. PK/PD variability necessitates a personalized approach to dosing in order to optimize therapeutic outcomes and minimize toxicity. TDM provides an avenue to refine dosing strategies based on individual patient characteristics. KEY MESSAGES:Through incorporation of TDM, treatment of hematological malignancies could move toward target concentration-driven dosing in clinical trials and regulatory frameworks. Establishing target concentrations for MTA requires solid exposure-response and exposure-toxicity analyses in the population of interest. To establish such reference ranges, large populational analyses are necessitated, underlining the importance of the incorporation of such endpoints into phase III trials. Economic restrictions, sample transportation logistics, turnaround times, and interpretation may hinder the application of a TDM-guided dosing approach in routine care. Ultimately, personalized TDM-guided dosing could improve patient outcomes and quality of life through minimizing toxicity.
INTRODUCTION:Evidence concerning the implementation of a therapeutic drug monitoring (TDM)-guided approach for optimizing isavuconazole exposure in onco-hematological pediatric patients is limited. The aim of this systematic review was to summarize the current evidence about the role that a TDM-guided strategy of isavuconazole may have in optimizing efficacy/safety outcomes of invasive fungal infection (IFI) treatment/prophylaxis among onco-hematological pediatric patients. METHODS:Two authors independently searched the PubMed-MEDLINE and Scopus databases up to 25 April 2025, to retrieve randomized controlled trials or observational studies providing real-life data assessing isavuconazole exposure according to a TDM-guided approach in pediatric patients, and evaluating the relationship between isavuconazole exposure and efficacy/safety outcomes. Data were independently extracted by the two authors, and the quality of the included studies was independently assessed by means of the Cochrane Risk of Bias Tool (RoB 2.0) in case of randomized controlled trials, and by means of the Newcastle-Ottawa scale in case of observational studies and case series. Mortality attributable to IFI and hepatotoxicity occurrence were selected as primary outcomes. Descriptive statistics were used for summarizing the retrieved data. RESULTS:After screening 577 articles, eight studies were included in the systematic review (five retrospective observational cohort studies and 3 case series; n = 116). Attainment of optimal isavuconazole exposure at first TDM assessment ranged from 36.7% to 83.3% of included patients, being underexposure reported in up to 40.0% of cases. Overall, mortality attributable to IFI occurred in 10 out of 59 patients (16.9%) in which this outcome was evaluated, being associated with isavuconazole underexposure only in 30.0% of cases. Hepatotoxicity occurred in 14 out of 78 included patients (17.9%), being related to isavuconazole overexposure in 50.0% of cases. CONCLUSION:Despite limited findings, our systematic review may support a potential role for a TDM-guided strategy in optimizing isavuconazole exposure among onco-hematological pediatric patients, particularly considering both the non-negligible proportion of cases who failed in attaining optimal exposure with standard dosing regimens.
BACKGROUND:Hepatocellular carcinoma (HCC) is one of the primary types of liver cancer, and the mortality trend of HCC patients is estimated to continue rising in the future. Chemotherapy drugs or targeted therapies are considered primary treatment modalities for intermediate-stage or advanced-stage HCC. Although these drugs can extend the survival rate of HCC patients, prolonged treatment often raises concerns about drug resistance or cancer recurrence, leading to undesirable therapeutic outcomes. Drug treatments generally involve promoting cytotoxicity and inhibiting oncogenic signaling pathways, and the response of cancer cells to drug-induced stress situations may potentially impact the effectiveness of treatment. The unfolded protein response (UPR) acts as a cellular stress response mechanism, activating pathways such as DNA repair and autophagy to help cellular survival when cells are damaged. It has also been shown that under sustained or excessive stress, UPR can control cell fate toward programmed cell death, such as apoptosis. Previous studies have found that activation of UPR plays an essential role in cancer cell growth and drug resistance. Various molecules or signaling pathways regulated by the UPR assist cancer cells in responding to anticancer drugs, enabling their survival during treatment. SUMMARY:The present review illustrated genetic molecules or signaling pathways controlled by the UPR and investigates their influence on liver cancer drugs. Moreover, the review also summarizes the partial effects of UPR, including lipid droplet formation and inflammatory stimulation, and their roles in HCC development and drug resistance, respectively. KEY MESSAGE:Unraveling and targeting ER stress provide potential therapeutic strategies for HCC treatment.
Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of chemotherapy. Low carnitine levels might negatively affect the development of CIPN. However, little is known of the course of carnitine levels during and directly after chemotherapy administration. Intervention studies using carnitine to prevent CIPN were contradictory, possibly due to different timing and route of carnitine supplementation. Better understanding of carnitine courses might improve future studies. This study aimed to investigate whether oxaliplatin-based chemotherapy administration affects blood and urinary levels of carnitine. We hypothesized that oxaliplatin increases renal excretion of carnitine, thereby causing a carnitine deficiency, which might contribute to the development of CIPN. METHODS:Ten patients, starting their first cycle of oxaliplatin-based chemotherapy, were enrolled in this observational pilot study. Blood and urinary samples were taken before, during and after infusion of oxaliplatin. Primary endpoints were changes in plasma and urinary concentrations of free carnitine and carnitine esters during administration of oxaliplatin-based chemotherapy. RESULTS:This study showed a significant decrease of both free carnitine and carnitine esters in plasma 2 h after the start of infusion of oxaliplatin-based chemotherapy. Moreover, a non-significant increase in urine carnitine concentration was seen during the chemotherapy infusion. CONCLUSION:The altered plasma and urinary concentrations of carnitine support our hypothesis that oxaliplatin causes increased renal excretion of carnitine, thereby lowering blood-carnitine levels and increasing urinary carnitine levels. With continued loss of carnitine over several chemotherapy cycles, this may result in the development of carnitine deficiency, which could contribute to the development of CIPN. These preliminary results provide a basis for hypothesis generation; larger longitudinal studies are required to confirm these findings and to determine the clinical relevance. .
INTRODUCTION:Doxorubicin (DOX), a potent anthracycline, is widely used in cancer therapy, but its effect is limited by doxorubicin-induced cardiotoxicity (DIC). Increasing evidence suggests that DIC is associated with ferroptosis, a cell death characterized by the iron-dependent accumulation of lipid peroxides. Although aerobic exercise is recommended for chemotherapy-related cardiac dysfunction, the extent to which its protective effects against DIC are mediated through the inhibition of ferroptosis remains largely unclear. The aim of this study was to elucidate the mechanism through which aerobic exercise attenuates DIC and provide theoretical support for promoting scientifically guided exercise in patients with DIC. METHODS:We conducted in vivo experiments involving 8 weeks of aerobic exercise during and after DOX treatment of C57BL/6J male mice, and in vitro experiments, H9c2 cells were treated with DOX and ferrostatin-1 (Fer-1, a ferroptosis inhibitor). Mice were randomly assigned into four groups: Control (C, n = 6), DOX (D, n = 10), aerobic exercise (E, n = 6) and DOX + aerobic exercise (DE, n = 10). Echocardiography was used to measure left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) to assess cardiac function in mice. ELISA kits were used to quantify serum biomarkers of myocardial injury, including cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), and lipid peroxidation markers, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Hematoxylin and eosin and Masson's trichrome were performed to evaluate myocardial structural damage. Fluorescent probes were used to detect ferrous iron (Fe2+), reactive oxygen species (ROS), and lipid peroxides in H9c2 cells. Western blotting was conducted to analyze ferroptosis-related proteins, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), acyl-CoA synthetase long-chain family member 4 (ACSL4), transferrin receptor 1 (TfR1), and ferritin heavy chain 1 (FTH1). RESULTS:DOX treatment significantly induced cardiac damage and dysfunction, as evidenced by disrupted myocardial tissue, increased myocardial fibrosis and cTnT levels, and decreased LVEF and LVFS. However, aerobic exercise effectively reduced cardiac structural and functional damage, and improved the rate of survival in mice. Furthermore, DOX-induced ferroptosis in cardiomyocytes both in vitro and in vivo, as marked by increased levels of Fe2+, ROS, and MDA, along with altered protein expression, including reduced FTH1 and SLC7A11 levels and increased ACSL4 levels. In contrast, aerobic exercise significantly mitigated these changes in vivo, and Fer-1 also effectively inhibited these effects in vitro. CONCLUSION:Collectively, this study demonstrates that aerobic exercise alleviates DIC via the inhibition of ferroptosis.
INTRODUCTION:This study aims to evaluate the efficacy and safety of cryoablation combined with pembrolizumab treatment versus cryoablation alone in patients with advanced non-small cell lung cancer (NSCLC). METHODS:This retrospective study was conducted from February 2018 to October 2021. A total of 90 patients with NSCLC (AJCC stage IIIB/IV) were included, with 36 patients receiving cryoablation combined with pembrolizumab (group A) and 54 patients receiving cryoablation alone (group B). The primary outcome measures included objective response rate (ORR), overall survival (OS), and progression-free survival (PFS), immune responses, and adverse events serving as secondary endpoints. Risk factors for OS and PFS were identified using univariate and multivariate analyses. RESULTS:No treatment-related deaths were observed. Group A demonstrated a higher ORR (75.0% vs. 61.1%), longer median OS (28.1 months vs. 24.2 months), and longer median PFS (12.8 months vs. 8.4 months) compared to Group B. Additionally, group A showed significant increases in CD3+, CD4+, and CD8+ T cells, and elevated levels of interleukin-2, interleukin-6, TNF-β, and interferon-γ. The multivariate analysis showed the combination of cryoablation and pembrolizumab was an independent prognostic factor for OS and PFS. CONCLUSIONS:Cryoablation combined with pembrolizumab significantly improves clinical outcomes in advanced NSCLC patients compared to cryoablation alone, highlighting the potential of this combination therapy in enhancing antitumor immunity and prolonging survival.
Introduction: Identifying the underlying mechanisms of immune checkpoint inhibitor resistance in patients with cachexia is a current challenge. Ghrelin is a peptide hormone that plays an important role in the metabolism of patients with cancer cachexia. Despite the importance of ghrelin in cancer cachexia, most previous studies on the subject have not distinguished between the forms of ghrelin. Methods: We retrospectively screened patients with advanced or recurrent non-small cell lung cancer receiving PD-1/PD-L1 inhibitor monotherapy. Active and inactive ghrelin levels were measured in 100 patients with available plasma samples at immune checkpoint inhibitor initiation. Cancer cachexia was defined as weight loss of at least 5% during the past 6 months or weight loss of at least 2% with a BMI <20. We analyzed the associations of the active and inactive ghrelin levels and active-to-inactive ghrelin ratio (AIR) with cancer cachexia. The prognostic impact of the active and inactive ghrelin levels and AIR were also analyzed. Results: Among 100 patients, 35 were diagnosed with cancer cachexia. The active ghrelin level and AIR were significantly associated with cancer cachexia, whereas the inactive ghrelin level was not. The active and inactive ghrelin levels and AIR were not associated with patient prognosis. Conclusion: The active ghrelin level and AIR were associated with cancer cachexia but not with patient prognosis. The function of the active and inactive forms of ghrelin may differ in cancer patients. The form of ghrelin should be clearly mentioned in relevant studies on cancer cachexia.
Background:Positron emission tomography (PET) with the use of 18F-fluorodeoxyglucose (FDG), implemented with low dosage Computer Tomography (CT), is to be considered as the most important evolution of imaging in the management and assessment of classical Hodgkin Lymphoma (cHL) patients.Summary:According to Lugano response criteria, FDG-PET is mandatory to define metabolic response to frontline therapy and moreover it is important in the definition of non-responders or refractory disease patients. Refractory disease is reported in about 15% of patients, with some variations based on the choice of first line chemotherapy and particularly in advanced stages up to 40% eventually relapse within 3 years.Key Messagges:The aim of this review is to highlight a practical way to use FDG-PET in the subset of HL, with some notes of its use in first line patients, and particularly centred on relapsed or refractory setting with a final focus of the evaluation of response by FDG-PET in the new treatment era of immunocheckpoint inhibitors (CPI).
Introduction: Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) therapy is indicated as first-line or neoadjuvant chemotherapy (NAC) for patients with advanced or metastatic urothelial carcinoma (UC). However, no studies reported ddMVAC therapy with pegfilgrastim (3.6 mg) in Japanese patients. We investigated the safety and efficacy of ddMVAC therapy with pegfilgrastim in patients with advanced or metastatic UC. Methods: A total of 43 patients received ddMVAC therapy with pegfilgrastim (3.6 mg) from February 2021 to December 2023. Among them, 25 and 18 patients received this regimen as first-line chemotherapy and NAC, respectively. We assessed toxicity and efficacy using Common Terminology Criteria for Adverse Events version 4.0 and Response Evaluation Criteria in Solid Tumors version 1.1, respectively. Results: The median number of ddMVAC therapy cycles was 3 (range: 1-5), with a total of 131 cycles. Cisplatin at the full dose without reduction was administered to 24 (56%) patients. Grade >= 3 hematologic toxicity occurred in 15 (35%) patients. Among them, anemia, neutropenia, thrombocytopenia, and febrile neutropenia were 13.9%, 9.3%, 11.7%, and 7.0%, respectively. Regarding non-hematologic toxicity, grade 3 appetite loss was observed in 2 (5%) patients. Complete response was observed in 7 (16%) patients and partial response in 26 patients (60%), yielding an objective response rate of 76%. Pathologic complete response (pCR; ypT0pN0) was observed in 3 (16.7%) patients and downstaging occurred in 13 (72.2%) patients. The median progression-free survival and overall survival of first-line treatment with ddMVAC were 18.6 months and not reached, respectively. Conclusion: The ddMVAC with pegfilgrastim (3.6 mg) reduced injection-related patient burden, caused fewer grade >= 3 adverse events, and demonstrated similar efficacy when compared to the original ddMVAC regimen that used granulocyte colony-stimulating factor for 7 consecutive days. (c) 2024 The Author(s).Published by S. Karger AG, Basel
Introduction: High-dose methotrexate (MTX) is used to treat pediatric acute lymphoblastic leukemia (ALL). The drug has a low therapeutic index and a highly interindividual variability in systemic exposure. These characteristics necessitate dose adjustments and therapeutic drug monitoring protocols, while population pharmacokinetic (POP/PK) models may enable more precise drug dosing. Therefore, we assessed the performance of external POP/PK models in ALL children receiving high-dose MTX. Methods: We retrospectively harvested clinical and laboratory data from ALL children during their first two cycles of chemotherapy. A POP/PK model was elaborated using the Monolix suite 2024R1. External models were selected from PUBMED based on strict inclusion/exclusion criteria, and their fit to the actual data was assessed by calculating bias (percentage prediction error [PE%]) and precision (percentage root mean squared error [RMSE%]). Results: Thirty-seven ALL children participated in the study (18 males, median age 5.1 years, range 1.7-15.2 years), and six external POP/PK models were chosen. Except for one model (median PE% value, -97.45%), all models exhibited acceptable bias (median PE% values, -4.17%-2.67%), despite none of them demonstrating good precision (median RMSE% values, 89.19%-120.40%). Conclusion: External models should be accurately evaluated before they are implemented in clinical practice, even when patients share very similar characteristics. (c) 2024 S. Karger AG, Basel
Introduction: This study investigates the efficacy of fucoidan combination with antibiotics, against single-species biofilms and mixed-species, individual planktonic, and coculture planktonic conditions of Methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii by time-kill curve analysis. Materials and Methods: Fucoidan, a sulfated polysaccharide, was purchased from Sigma-Aldrich, USA. Clinical isolates of MRSA and A. baumannii from diabetic foot ulcers (DFUs) were used, and single-species biofilms and mixed-species biofilms were developed to assess susceptibility to the treatments using MIC, MBC, minimum biofilm inhibitory concentration, minimum biofilm eradication concentration, and time-kill kinetics assays. Cytotoxicity was assessed using MTT assays on human skin fibroblast cells (HSF-PI 16). Results: The study determined the geometric mean MIC and MBC values for gentamicin, imipenem, and fucoidan in MRSA and A. baumannii cultures, both individually and in co-cultures. The MIC and MBC values were significantly lower under co-culture conditions, indicating enhanced antimicrobial efficacy. Synergy between fucoidan, gentamicin, and imipenem was confirmed through time-kill assays, which showed complete inhibition of bacterial growth and effective biofilm eradication, particularly in mixed-species biofilms. Fucoidan demonstrated low cytotoxicity at optimal concentrations, highlighting their potential as a therapeutic strategy against biofilm-associated infections in DFUs. Conclusion: The study concludes that fucoidan, in combination with gentamicin and imipenem, effectively disrupts mixed-species biofilms of MRSA and A. baumannii, suggesting fucoidan-based therapies could improve outcomes for DFU patients, warranting further clinical investigation. (c) 2024 S. Karger AG, Basel
Introduction: We report the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of a multikinase inhibitor (TG02 capsule) as a new therapy for patients with recurrent high-grade gliomas in China. Methods: This is a single-center, dose-escalation, open-label phase I study, which enrolled patients with recurrent high-grade gliomas who failed to temozolomide. Patients were assigned sequentially into different dose groups and received TG02 every 4 weeks. The dose was increased in a traditional 3 + 3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose (MTD). Results: Twelve patients (8 glioblastomas, 4 diffuse astrocytoma) were enrolled between May 2019 and November 2021. Three patients received 100 mg and 9 received 150 mg TG02 twice a week. The plasma concentration of TG02 reached the maximum at 2 h after administration, and the elimination half-life was about 7 h. No DLT occurred and MTD was not defined in this study. Eleven patients had one or more investigator-assessed treatment-related adverse events (TRAEs). The most frequent TRAEs were vomiting (91.7%) and diarrhea (75.0%), and 50% of the patients had grade 3 or 4 adverse events. There were no treatment-related deaths. The median progression-free survival and overall survival were 1.77 (95% confidence interval [CI]: 0.82-4.24) and 9.63 (95% CI: 2.66-not estimated) months, respectively. Conclusions: TG02 capsule 150 mg twice a week is safe and tolerable in Chinese patients with recurrent high-grade gliomas. Patients who failed to temozolomide showed obvious tumor reduction when switching to TG02 capsule. The efficacy of recurrent gliomas warrants further investigation.
Introduction: Our study aimed to identify relevant features associated with the reprisal of antineoplastic treatment in patients with solid cancers after unplanned admittance to the intensive care unit (ICU) and to assess 60th-month survival in patients with solid neoplasms admitted to the ICU. Methods: This single-centre retrospective study of critically ill patients with active cancers was performed over a 13-year period (2005-2018). Patients' characteristics, overall survival, and antineoplastic treatment reprisal were extracted from digital medical files and compared. Results: 134 patients were included in the study. Solid neoplasms were mostly localised to the head and neck (n = 53) followed by lung cancers (n = 29). Sepsis was the leading cause of ICU admission (62.1%) with 41/82 patients presenting with septic shock. Antineoplastic treatments were resumed in 40 patients. An age <= 60 years and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) <= 1 were found to be predictors for treatment reprisal, with odd ratios of, respectively, 2.83 (95% CI, 1.15-6.99) and 5.45 (95% CI, 2.01-14.82); area under the ROC curve of 72% (95% CI, 63-81%). Survival after the immediate discharge from the ICU was 101/134 (75%) and the 60-month survival rate was 29% and significantly higher in the treatment-reprisal group. Conclusions: Age and ECOG PS were found to be predictors for treatment reprisal in patients with solid neoplasms admitted to the ICU. The latter benefits from better long-term survival.
